The citation and/or discussion of cited references in this section and throughout the specification is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the present invention.
Dystonia is characterized by twisting movements and abnormal postures (Fahn, S. Adv. Neurol. (1988) 50: 1-8). At least 15 different types of dystonia can be distinguished genetically, most of which are inherited in an autosomal dominant (AD) manner with reduced penetrance.
DYT1, 2, 4, 6, 7 and 13, comprise primary forms, where dystonia is the only neurologic feature (deCarvalho Aguiar, P. M. and Ozelius, L. J., Lancet Neurol. (2002) 1: 316-25). The genetic basis for only one of these, DYT1, responsible for most cases of early onset generalized dystonia, has been identified (Ozelius, L. J. et al., Nat. Gene. (1997) 17: 40-8).
DYT6 is dominantly inherited with penetrance of about 60% independent of gender. It is characterized by an average onset age of 16.1 years, cranial or cervical presentation in about half of the cases and frequent progression to involve multiple body regions. First mapped to a 40cM (peri-contromeric) region on chromosome 8 in two Amish-Mennonite families (M and C) (Almasy, L. et al., Ann. Neurol. (1997) 42: 670-3), an additional Amish-Mennonite family (R) was shown to share the DYT6 disease haplotype and all three families were descended from several “Old Order Amish” ancestral pairs (Sanders-Pullman, R. et al., Am. J. Med. Genet. A (2007) 143A: 2098-105). The linked region was narrowed to 23cM between markers D8S2317 and D8S2323; this region contains ˜120 genes (March 2006 UCSC human genome assembly, available on the WorldWideWeb at genome.ucsc.edu ) (Sanders-Pullman, R. et al., Am. J. Med. Genet. A(2007) 143A: 2098-105).